This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There are four serotypes of dengue virus. Many antibodies elicited in infected patients neutralize only one serotype. However, serotype-specific antibodies can facilitate the entry of other dengue serotypes into myeloid cells by mediating attachment of the virus to the Fc receptors on those cells. Antibody-dependent enhancement of infection (ADE) significantly worsens the severity of disease. Obtaining a detailed molecular landscape of all four dengue serotypes will allow us to map the differences between serotypes that are responsible for ADE. Flaviviruses use their envelope protein, E, to bind a receptor and enter cells by endocytosis. The reduced pH of an endosome triggers a conformational rearrangement in E. The energy released in this conformational rearrangement is used to bend the viral lipid membrane towards the endosomal membrane, resulting in fusion of the two membranes. Membrane fusion delivers the viral genome into the cytoplasm and is therefore a key step in viral entry. Building on our structural studies of E from dengue and West Nile viruses in the pre- and postfusion states, we aim to complete our picture of flaviviral membrane fusion by determining the structures of the full-length E ectodomain. We also aim to determine the structure of E in complex with various peptides with therapeutic antiviral properties. Our work will provide a framework for the rational design and screening of drugs that inhibit viral entry. There are currently no treatments or vaccines available for West Nile or dengue virus, which are both emerging global health threats. Vaccine design has been hampered by the high variability of most neutralizing epitopes and by ADE, which is thought to be a major cause of mortality from dengue fever. In an effort to guide vaccine design, we will study the structural basis for neutralization by antibodies that bind conserved epitopes in flaviviral envelope proteins.